Safety · 5 routes · Labels read 2026-08-15
HRT side effects, one route at a time
Every consumer page on this subject gives you one list. A patch, a pill, a gel, a spray and a vaginal insert are five different drugs by the only measure that counts here, which is what their own trials measured. Below, each route is taken from its own FDA-approved label with that label's own placebo column attached. Read the placebo column first. On the patch, headache is the most common reaction at four of the five doses and runs 23.6 percent on placebo. On the gel it is 9.5 percent against 2.7. And the plain estradiol tablet most women are actually handed publishes no percentage for anything.
What are HRT side effects?
HRT side effects are the unwanted effects of replacing estrogen, and where a progestogen is prescribed alongside it, of the progestogen too. Raising circulating estrogen acts on receptors in breast tissue, the uterine lining, blood vessels and the brain, which is why the labelled reactions cluster into breast tenderness, bleeding changes, headache and mood, with a separate group of reactions belonging to the delivery method rather than the hormone. The two groups behave differently: a headache rate can be compared against the placebo arm of the same trial, while an application-site rash on a patch has no placebo equivalent because only the patch has an adhesive.
Every rate on this page comes from an FDA-approved product. Compounded estradiol and compounded progesterone, which several telehealth platforms dispense, are not FDA-approved and have no adverse-reaction table, because a compounded preparation never runs a registration trial. What bioidentical actually means.
Every route, with its label's own placebo column
One caution before the tables, and it is the reason they are not merged into a single grid. Each label filters its own table differently. Vagifem 10 mcg and Bijuva print only reactions that were MORE common on the drug than on placebo, so a reaction that ran higher on placebo is invisible in those two by construction. The patch and gel labels filter on frequency alone and therefore keep the rows where placebo won. Compare within a table, and read across tables as direction rather than as a ranking.
Pill
Bijuva (estradiol and progesterone) capsules, Mayne Pharma. Label posted 2026-04-24, read 2026-08-15. One-year trial in 1,835 postmenopausal women, 1,684 on active treatment and 151 on placebo. Around 70 percent of the treated women were dosed for 326 days or more.
| Reaction | Bijuva 0.5 mg / 100 mgn=424 | Bijuva 1 mg / 100 mgn=415 | Placebon=151 |
|---|---|---|---|
| Breast tenderness | 4%(17) | 10.4%(43) | 0.7%(1) |
| Headache | 4%(17) | 3.4%(14) | 0.7%(1) |
| Nausea | 3.5%(15) | 2.2%(9) | 0.7%(1) |
| Vaginal bleeding | 2.4%(10) | 3.4%(14) | 0%(0) |
| Vaginal discharge | 1.9%(8) | 3.4%(14) | 0.7%(1) |
| Pelvic pain | 2.8%(12) | 3.1%(13) | 0%(0) |
Which rows made the table: Reported at 3 percent or more in either Bijuva group AND numerically more common than placebo. Reactions that ran higher on placebo cannot appear.
Patch
Vivelle-Dot (estradiol transdermal system), Sandoz Inc. Label posted 2023-11-17, read 2026-08-03. Pooled trial programme reported across five dose arms plus a placebo arm of 157 patients.
| Reaction | 0.025 mg/dayn=47 | 0.0375 mg/dayn=130 | 0.05 mg/dayn=103 | 0.075 mg/dayn=46 | 0.1 mg/dayn=132 | Placebon=157 |
|---|---|---|---|---|---|---|
| Weight increased | 8.5%(4) | 3.8%(5) | 1.9%(2) | 4.3%(2) | 0%(0) | 1.9%(3) |
| Headache | 14.9%(7) | 26.9%(35) | 31.1%(32) | 50%(23) | 25.8%(34) | 23.6%(37) |
| Breast tenderness | 17%(8) | 7.7%(10) | 7.8%(8) | 6.5%(3) | 12.9%(17) | 0%(0) |
| Intermenstrual bleeding | 6.4%(3) | 6.9%(9) | 5.8%(6) | 0%(0) | 10.6%(14) | 4.5%(7) |
| Depression | 10.6%(5) | 3.1%(4) | 6.8%(7) | 0%(0) | 3%(4) | 3.8%(6) |
| Insomnia | 6.4%(3) | 4.6%(6) | 3.9%(4) | 4.3%(2) | 1.5%(2) | 5.7%(9) |
| Nausea | 4.3%(2) | 6.2%(8) | 3.9%(4) | 0%(0) | 5.3%(7) | 3.2%(5) |
| Constipation | 4.3%(2) | 3.8%(5) | 3.9%(4) | 6.5%(3) | 1.5%(2) | 2.5%(4) |
| Back pain | 8.5%(4) | 7.7%(10) | 8.7%(9) | 8.7%(4) | 10.6%(14) | 6.4%(10) |
| Hot flushes | 6.4%(3) | 0%(0) | 2.9%(3) | 0%(0) | 0%(0) | 3.8%(6) |
Which rows made the table: Reported at 5 percent or more, regardless of whether the investigator judged the reaction related to the drug. No placebo-comparison filter. Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups).
Gel
EstroGel 0.06% (estradiol gel), Ascend Therapeutics US, LLC. Label posted 2026-05-29, read 2026-08-15. Two well-controlled 12-week trials, intent-to-treat safety population.
| Reaction | EstroGel 1.25 g/dayn=168 | Placebon=73 |
|---|---|---|
| Breast pain | 10.7% | 8.2% |
| Headache | 9.5% | 2.7% |
| Flatulence | 5.4% | 4.1% |
Which rows made the table: Reported at 5 percent or more in the EstroGel group. No placebo-comparison filter, so a row can run higher on placebo and still be printed. Application site reactions were reported by 0.6 percent of patients who received 1.25 g of EstroGel.
Spray
Evamist (estradiol) transdermal spray, Padagis US LLC. Label posted 2024-10-29, read 2026-08-15. One 12-week randomized placebo-controlled trial in 454 women, run as three separate dose comparisons.
| Reaction | 1 spray, placebon=77 | 1 sprayn=76 | 2 sprays, placebon=76 | 2 spraysn=74 | 3 sprays, placebon=75 | 3 spraysn=76 |
|---|---|---|---|---|---|---|
| Headache | 5%(4) | 9%(7) | 7%(5) | 12%(9) | 9%(7) | 11%(8) |
| Breast tenderness | 0%(0) | 5%(4) | 5%(4) | 7%(5) | 0%(0) | 5%(4) |
| Nipple pain | 0%(0) | 3%(2) | 0%(0) | 7%(5) | 0%(0) | 1%(1) |
| Nausea | 7%(5) | 1%(1) | 1%(1) | 3%(2) | 5%(4) | 3%(2) |
| Nasopharyngitis | 1%(1) | 5%(4) | 3%(2) | 4%(3) | 1%(1) | 1%(1) |
| Back pain | 1%(1) | 3%(2) | 3%(2) | 5%(4) | 1%(1) | 3%(2) |
| Arthralgia | 1%(1) | 1%(1) | 5%(4) | 1%(1) | 0%(0) | 4%(3) |
Which rows made the table: Reported at 5 percent or more in ANY treatment group, including the placebo groups. That is why rows appear where placebo is the higher number. Application site reactions were reported in 3 out of 226 (1.3 percent) women treated with Evamist.
Vaginal
Vagifem 10 mcg (estradiol vaginal inserts), Novo Nordisk. Label posted 2025-02-10, read 2026-08-15. One 12-month randomized double-blind placebo-controlled study, 309 postmenopausal women randomized.
| Reaction | Vagifem 10 mcgn=205 | Placebon=103 |
|---|---|---|
| Vulvovaginal mycotic infection | 8%(17) | 3%(3) |
| Vulvovaginal pruritus | 8%(16) | 2%(2) |
| Back pain | 7%(14) | 2%(2) |
| Diarrhea | 5%(11) | 0%(0) |
Which rows made the table: Reported at 5 percent or more in the Vagifem group AND greater than placebo. Reactions that ran higher on placebo cannot appear.
The pill most women are actually prescribed publishes no rate at all
The oral table above is Bijuva (estradiol and progesterone) capsules, a combined capsule with a modern label. Generic estradiol tablets are a different document. We read the Estradiol tablets, USP label posted 2026-07-01 and read it again on 2026-08-15. Its adverse reactions section is a list of reactions organised by body system, from genitourinary through to eyes, with no frequency attached to any of them and no placebo comparison anywhere in the document. It is in the pre-2006 label format, which never required one.
That is worth saying plainly rather than filling the gap with a number from a different product. If you are on a generic estradiol tablet and you want to know how often a reaction happens, the label you were dispensed does not answer the question, and neither does anyone quoting it. The nearest evidence is the oral arm of the trials above, run on a different formulation.
There is no route table for pellets, and that is the finding
Estradiol pellets are marketed hard by clinics that implant them, so their absence from the tables above needs an explanation. There is no FDA-approved estradiol pellet marketed in the United States. DailyMed lists one estradiol pellet product, ESTRA-25 and ESTRA-50 (estradiol pellet), and its approval element carries the marketing category Export only (C73590). Checked 2026-08-15.
A pellet implanted in a US clinic is therefore a compounded preparation. That is a statement about what evidence exists rather than an accusation: a compounded product does not run the registration trial that produces a placebo-controlled table, so there is no rate to compare, because nobody measured one. It also cannot be removed once it is in, which is the practical difference from every other route on this page. FDA on human drug compounding.
What are the first signs that HRT is working?
No label publishes an onset timeline. One label publishes something better: a per-timepoint efficacy table with a placebo arm. In the EstroGel vasomotor study, 72 women on the gel and 73 on placebo were assessed at weeks 4 and 12, with week 4 the primary timepoint. Starting from 10.33 hot flushes a day, the treated group was down 5.91 a day by week 4. The placebo group was down 5.06.
The gap between them at that point was 0.85 flushes a day, p = 0.019, widening to 1.71 by week 12. So the first weeks feel like something is happening whether or not the drug is doing it, and the honest read of the label is that four weeks is the point at which the trial itself was willing to judge. Feeling better fast is not proof the dose is right, and feeling nothing at week two is not proof it is wrong.
Why am I feeling tired when I'm on HRT?
Check which half of the regimen is doing it. If you take micronized progesterone, the sedation is on the label: the Prometrium precautions state that the capsules "may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery", and instruct that the dose be taken at bedtime. A prescriber moving your progesterone to the evening is following the label rather than improvising. The full progesterone table.
On the estrogen side the answer is thinner, and the thinness is the answer. Fatigue appears in the postmarketing sections of the EstroGel and Evamist labels, which means it has been reported voluntarily from a population of unknown size and no frequency can be estimated from it. Insomnia has a real number: on the patch label it is 6.4 percent at the lowest dose against 5.7 percent on placebo, and it comes in below the placebo rate at four of the five doses. Anyone telling you estrogen reliably causes or cures fatigue is going past the evidence in both directions.
What settles, what warrants a call, and what is an emergency
No FDA label publishes a resolution timeframe for any reaction on this page, so any page giving you one in weeks is quoting a forum rather than a document. What the labels do publish is how long their trials ran, which is the outer bound on what anyone measured: 12 weeks for the EstroGel and Evamist programs, 12 months for Vagifem, one year for Bijuva. Breast tenderness and bleeding changes are the reactions that appear across all of them, and they are also the reactions a prescriber will most often ask you to give a full cycle before changing anything.
One allergy note that catches people out, because it has nothing to do with hormones: the Prometrium label states that "This product contains peanut oil and should not be used if you are allergic to peanuts."
Is it better to go through menopause without HRT?
If your symptoms are not bothering you, no guideline tells you to treat them. If they are, The Menopause Society's 2022 position statement calls hormone therapy the most effective treatment available for vasomotor symptoms and for genitourinary syndrome of menopause, and says it prevents bone loss and fracture. The benefit-risk ratio is favorable under 60 or within 10 years of menopause onset, and less favorable past that. The stratified version, with the absolute numbers.
For women who cannot take estrogen or choose not to, ACOG names antidepressants, gabapentin and clonidine as prescription options for hot flashes, and a non-hormonal neurokinin antagonist is approved for the same indication. What the non-hormonal route costs and who prescribes it. ACOG also states in the same document that forms of therapy not taken by mouth may carry less risk of deep vein thrombosis than oral forms, which is the route point restated by a second body.
What insurance covers HRT?
Of the 13women's-wing platforms whose prices we verify, 3 bill insurance (Midi Health, Gennev, Elektra Health) and the rest are cash-pay whatever plan you hold. That is the split that decides your bill, ahead of your formulary. Generic estradiol and micronized progesterone are widely covered when a billing clinician writes them; compounded preparations generally are not, because a compounded preparation is not an FDA-approved product. Which platforms bill and what the cash route costs.
FAQ
HRT side effects, answered
What are the side effects of HRT?
They differ by route, which is the part most lists leave out. On the Vivelle-Dot (estradiol transdermal system) label, the reactions at 5 percent or more across five dose arms are headache, breast tenderness, intermenstrual bleeding, back pain, depression, insomnia, nausea, constipation, hot flushes and weight increase, with headache at 23.6 percent in the placebo arm as well. On the EstroGel 0.06% (estradiol gel) label, three reactions clear 5 percent: breast pain at 10.7 percent against 8.2 on placebo, headache at 9.5 against 2.7, and flatulence at 5.4 against 4.1. On the Vagifem 10 mcg (estradiol vaginal inserts) label, the reactions are local: vulvovaginal yeast infection at 8 percent and vulvovaginal itching at 8 percent. Plain estradiol tablets publish no percentage for any reaction.
Is it better to go through menopause without HRT?
For a woman without bothersome symptoms, doing nothing is a legitimate choice and no guideline says otherwise. For a woman with bothersome hot flashes, The Menopause Society's 2022 position statement calls hormone therapy the most effective treatment there is for vasomotor symptoms and for genitourinary syndrome of menopause, and says it prevents bone loss and fracture. The same statement puts the benefit-risk ratio in favor of treatment for women under 60 or within 10 years of menopause onset, and calls it less favorable past that window. For women who cannot take estrogen or do not want to, ACOG names antidepressants, gabapentin and clonidine as prescription options for hot flashes, and a non-hormonal neurokinin antagonist is also approved for this indication.
What are the first signs that HRT is working?
No FDA label publishes an onset timeline, and the one label with a per-timepoint efficacy table shows why that question is harder than it sounds. In the placebo-controlled study in 145 postmenopausal women aged 29 to 67, 12 weeks. behind the EstroGel label, efficacy was assessed at weeks 4 and 12, with week 4 the primary timepoint. At week 4 the treated group lost 5.91 hot flushes a day from a baseline of 10.33. The placebo group lost 5.06. The difference between them was 0.85 flushes a day, p = 0.019. So feeling better in the first weeks is real and expected, and it is not by itself evidence that the dose is right, because the placebo arm felt better too.
Why am I feeling tired when I'm on HRT?
If your regimen includes micronized progesterone, the sedating component is labelled. The Prometrium label states that the capsules "may cause transient dizziness and drowsiness" and instructs that they be taken as a single daily dose at bedtime, which is the reason a prescriber moves them to evening. Fatigue on the estrogen side is different: it appears in the postmarketing sections of the EstroGel and Evamist labels, which means it has been reported voluntarily and no frequency can be reliably estimated from it. Insomnia, which produces the same complaint by a different route, appears on the estradiol patch label at 6.4 percent at the lowest dose against 5.7 percent on placebo, and lower than placebo at four of the five doses.
What insurance covers HRT?
Of the 13 women's-wing platforms whose prices we verify, 3 bill insurance and the rest are cash-pay. That split matters more than the plan you hold, because a cash-pay telehealth platform will not bill your insurer whatever your coverage is. FDA-approved generic estradiol and micronized progesterone are widely covered on commercial formularies when prescribed through a clinician who bills; compounded preparations generally are not, because a compounded preparation is not an FDA-approved product. Our insurance page lists which platforms bill and what the cash alternative costs.
Which HRT side effects mean I should seek care immediately?
Chest pain, shortness of breath, swelling or pain in one leg, sudden severe headache, weakness on one side, and any sudden change in vision. Those map to the venous thromboembolism and stroke warnings that appear on every systemic estrogen label. The estrogen labels are explicit about the eye symptoms: the EstroGel label instructs that the drug be discontinued pending examination for "sudden partial or complete loss of vision or a sudden onset of proptosis, diplopia, or migraine". Do not wait for a scheduled telehealth message on any of these. Seek emergency care.
Sources
- Bijuva (estradiol and progesterone) capsules prescribing information, Mayne Pharma, DailyMed (label posted 2026-04-24, read 2026-08-15).
- Vivelle-Dot (estradiol transdermal system) prescribing information, Sandoz Inc, DailyMed (label posted 2023-11-17, read 2026-08-03).
- EstroGel 0.06% (estradiol gel) prescribing information, Ascend Therapeutics US, LLC, DailyMed (label posted 2026-05-29, read 2026-08-15).
- Evamist (estradiol) transdermal spray prescribing information, Padagis US LLC, DailyMed (label posted 2024-10-29, read 2026-08-15).
- Vagifem 10 mcg (estradiol vaginal inserts) prescribing information, Novo Nordisk, DailyMed (label posted 2025-02-10, read 2026-08-15).
- Estradiol tablets, USP prescribing information, DailyMed (label posted 2026-07-01, read 2026-08-15). Publishes no adverse-reaction rate.
- ACOG, The Menopause Years
- The Menopause Society, 2022 hormone therapy position statement (PMID 35797481)
- Vinogradova et al, HRT and risk of venous thromboembolism, BMJ 2019 (PMID 30626577)
- FDA, human drug compounding
This is general information, not medical advice. Hormone therapy is a prescription treatment and which reaction matters for you, at your dose and by your route, is a decision for you and a licensed clinician. Written and reviewed by Iacob Pastina. Back to the Safety Center.
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